Optimal boundary control of a linear parabolic evolution system

We consider the optimal boundary control of a linear parabolic boundary value problem. Firstly, the problem is formulated as an optimization problem with the system state governed by a parabolic partial differential equation. Based on the formulation for the variation of the cost functional, a gradient-type optimization technique utilizing the finite element method is then developed to solve the constrained optimization problem. Finally, a numerical example is given and the results show that the method of solution is robust

Temperature and heat stress in a concrete column at early ages

The temperature development and the stress generated in a cylindrical column of concrete are investigated. The problem is essentially two-dimensional, and is solved using a finite element package. Adiabatic temperature data from four different concrete mixes are used and the influences on the temperature and stress development due to the use of silica fumes or slag in the mixes are discussed

Fr-TM-align: a new protein structural alignment method based on fragment alignments and the TM-score

©2008 Pandit and Skolnick; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. This article is available from: http://www.biomedcentral.com/1471-2105/9/531doi:10.1186/1471-2105-9-531Background: Protein tertiary structure comparisons are employed in various fields of contemporary structural biology. Most structure comparison methods involve generation of an initial seed alignment, which is extended and/or refined to provide the best structural superposition between a pair of protein structures as assessed by a structure comparison metric. One such metric, the TM-score, was recently introduced to provide a combined structure quality measure of the coordinate root mean square deviation between a pair of structures and coverage. Using the TM-score, the TM-align structure alignment algorithm was developed that was often found to have better accuracy and coverage than the most commonly used structural alignment programs; however, there were a number of situations when this was not true. Results: To further improve structure alignment quality, the Fr-TM-align algorithm has been developed where aligned fragment pairs are used to generate the initial seed alignments that are then refined using dynamic programming to maximize the TM-score. For the assessment of the structural alignment quality from Fr-TM-align in comparison to other programs such as CE and TMalign, we examined various alignment quality assessment scores such as PSI and TM-score. The assessment showed that the structural alignment quality from Fr-TM-align is better in comparison to both CE and TM-align. On average, the structural alignments generated using Fr-TM-align have a higher TM-score (~9%) and coverage (~7%) in comparison to those generated by TM-align. Fr- TM-align uses an exhaustive procedure to generate initial seed alignments. Hence, the algorithm is computationally more expensive than TM-align. Conclusion: Fr-TM-align, a new algorithm that employs fragment alignment and assembly provides better structural alignments in comparison to TM-align. The source code and executables of Fr- TM-align are freely downloadable at: http://cssb.biology.gatech.edu/skolnick/files/FrTMalign/

Reconciling conflicting evidence for the cause of the observed early 21st century Eurasian cooling

It is now well established that the Arctic is warming at a faster rate than the global average. This warming, which has been accompanied by a dramatic decline in sea ice, has been linked to cooling over the Eurasian subcontinent over recent decades, most dramatically during the period 1998–2012. This is a counter-intuitive impact under global warming given that land regions should warm more than ocean (and the global average). Some studies have proposed a causal teleconnection from Arctic sea-ice retreat to Eurasian wintertime cooling; other studies argue that Eurasian cooling is mainly driven by internal variability. Overall, there is an impression of strong disagreement between those holding the “ice-driven” versus “internal variability” viewpoints. Here, we offer an alternative framing showing that the sea ice and internal variability views can be compatible. Key to this is viewing Eurasian cooling through the lens of dynamics (linked primarily to internal variability with some potential contribution from sea ice; cools Eurasia) and thermodynamics (linked to sea-ice retreat; warms Eurasia). This approach, combined with recognition that there is uncertainty in the hypothesized mechanisms themselves, allows both viewpoints (and others) to co-exist and contribute to our understanding of Eurasian cooling. A simple autoregressive model shows that Eurasian cooling of this magnitude is consistent with internal variability, with some periods exhibiting stronger cooling than others, either by chance or by forced changes. Rather than posit a “yes-or-no” causal relationship between sea ice and Eurasian cooling, a more constructive way forward is to consider whether the cooling trend was more likely given the observed sea-ice loss, as well as other sources of low-frequency variability. Taken in this way both sea ice and internal variability are factors that affect the likelihood of strong regional cooling in the presence of ongoing global warming.</p

Reconciling conflicting evidence for the cause of the observed early 21st century Eurasian cooling

It is now well established that the Arctic is warming at a faster rate than the global average. This warming, which has been accompanied by a dramatic decline in sea ice, has been linked to cooling over the Eurasian subcontinent over recent decades, most dramatically during the period 1998–2012. This is a counter-intuitive impact under global warming given that land regions should warm more than ocean (and the global average). Some studies have proposed a causal teleconnection from Arctic sea-ice retreat to Eurasian wintertime cooling; other studies argue that Eurasian cooling is mainly driven by internal variability. Overall, there is an impression of strong disagreement between those holding the “ice-driven” versus “internal variability” viewpoints. Here, we offer an alternative framing showing that the sea ice and internal variability views can be compatible. Key to this is viewing Eurasian cooling through the lens of dynamics (linked primarily to internal variability with some potential contribution from sea ice; cools Eurasia) and thermodynamics (linked to sea-ice retreat; warms Eurasia). This approach, combined with recognition that there is uncertainty in the hypothesized mechanisms themselves, allows both viewpoints (and others) to co-exist and contribute to our understanding of Eurasian cooling. A simple autoregressive model shows that Eurasian cooling of this magnitude is consistent with internal variability, with some periods exhibiting stronger cooling than others, either by chance or by forced changes. Rather than posit a “yes-or-no” causal relationship between sea ice and Eurasian cooling, a more constructive way forward is to consider whether the cooling trend was more likely given the observed sea-ice loss, as well as other sources of low-frequency variability. Taken in this way both sea ice and internal variability are factors that affect the likelihood of strong regional cooling in the presence of ongoing global warming.</p

A fatal case of oral intoxication by mustard gas

Opisan je slučaj peroralne intosikacije iperitom u namjeri samoubojstva i iznesen obdukcioni nalaz. Ukratko su izneseni neki toksikološki pogledi na otrovanje iperifom, te klinički simptomi i patomorfološke promjene kod intoksikacije ovim otrovom.A case is presented of a man aged 27 who swallowed 50 g of mustard gas (dichlor-diethylsulphide) in order to commit suicide. Although immediately treated at the Internal Clinic of the Medical Faculty, he died 8 hours and 20 minutes after taking the poison. A postmortem examination carried out 19 hours after death, as well as histological findings showed congestion and oedema of the brain, fragmentation of cardiac muscle, oedema of mucous membranes of the upper part of gastrointestinal tract, oedema of larynx and epiglotis, oedema of the liver, and congestion of the spleen, adrenal glands, and kidneys. A microscopic examination of the lung tissue revealed hemorrhages probably due to the irritative effect of the poison

Comparison of IRES and F2A-Based Locus-Specific Multicistronic Expression in Stable Mouse Lines

Efficient and stoichiometric expression of genes concatenated by bi- or multi-cistronic vectors has become an invaluable tool not only in basic biology to track and visualize proteins in vivo, but also for vaccine development and in the clinics for gene therapy. To adequately compare, in vivo, the effectiveness of two of the currently popular co-expression strategies - the internal ribosome entry site (IRES) derived from the picornavirus and the 2A peptide from the foot-and-mouth disease virus (FDMV) (F2A), we analyzed two locus-specific knock-in mouse lines co-expressing SRY-box containing gene 9 (Sox9) and enhanced green fluorescent protein (EGFP) linked by the IRES (Sox9IRES-EGFP) or the F2A (Sox9F2A-EGFP) sequence. Both the constructs expressed Sox9 and EGFP proteins in the appropriate Sox9 expression domains, with the IRES construct expressing reduced levels of EGFP compared to that of the F2A. The latter, on the other hand, produced about 42.2% Sox9-EGFP fusion protein, reflecting an inefficient ribosome ‘skipping’ mechanism. To investigate if the discrepancy in the ‘skipping’ process was locus-dependent, we further analyzed the FLAG3-Bapx1F2A-EGFP mouse line and found similar levels of fusion protein being produced. To assess if EGFP was hindering the ‘skipping’ mechanism, we examined another mouse line co-expressing Bagpipe homeobox gene 1 homolog (Bapx1), Cre recombinase and EGFP (Bapx1F2A-Cre-F2A-EGFP). While the ‘skipping’ was highly efficient between Bapx1 and Cre, the ‘skipping’ between Cre and EGFP was highly inefficient. We have thus demonstrated in our comparison study that the efficient and close to equivalent expression of genes linked by F2A is achievable in stable mouse lines, but the EGFP reporter may cause undesirable inhibition of the ‘skipping’ at the F2A sequence. Hence, the use of other reporter genes should be explored when utilizing F2A peptides

Equal Graph Partitioning on Estimated Infection Network as an Effective Epidemic Mitigation Measure

Controlling severe outbreaks remains the most important problem in infectious disease area. With time, this problem will only become more severe as population density in urban centers grows. Social interactions play a very important role in determining how infectious diseases spread, and organization of people along social lines gives rise to non-spatial networks in which the infections spread. Infection networks are different for diseases with different transmission modes, but are likely to be identical or highly similar for diseases that spread the same way. Hence, infection networks estimated from common infections can be useful to contain epidemics of a more severe disease with the same transmission mode. Here we present a proof-of-concept study demonstrating the effectiveness of epidemic mitigation based on such estimated infection networks. We first generate artificial social networks of different sizes and average degrees, but with roughly the same clustering characteristic. We then start SIR epidemics on these networks, censor the simulated incidences, and use them to reconstruct the infection network. We then efficiently fragment the estimated network by removing the smallest number of nodes identified by a graph partitioning algorithm. Finally, we demonstrate the effectiveness of this targeted strategy, by comparing it against traditional untargeted strategies, in slowing down and reducing the size of advancing epidemics

Discovery of a Non-Peptidic Inhibitor of West Nile Virus NS3 Protease by High-Throughput Docking

An estimated 2.5 billion people are at risk of diseases caused by dengue and West Nile virus. As of today, there are neither vaccines to prevent nor drugs to cure the severe infections caused by these viruses. The NS3 protease is one of the most promising targets for drug development against West Nile virus because it is an essential enzyme for viral replication and because success has been demonstrated with the closely related hepatitis C virus protease. We have discovered a small molecule that inhibits the NS3 protease of West Nile virus by computer-aided high-throughput docking, and validated it using three experimental techniques. The inhibitor has potential to be developed to a drug candidate to combat West Nile virus infections

Oral particle uptake and organ targeting drives the activity of amphotericin B nanoparticles

There are very few drug delivery systems that target key organs via the oral route, as oral delivery advances normally address gastrointestinal drug dissolution, permeation, and stability. Here we introduce a nanomedicine in which nanoparticles, while also protecting the drug from gastric degradation, are taken up by the gastrointestinal epithelia and transported to the lung, liver, and spleen, thus selectively enhancing drug bioavailability in these target organs and diminishing kidney exposure (relevant to nephrotoxic drugs). Our work demonstrates, for the first time, that oral particle uptake and translocation to specific organs may be used to achieve a beneficial therapeutic response. We have illustrated this using amphotericin B, a nephrotoxic drug encapsulated within <i>N</i>-palmitoyl-<i>N</i>-methyl-<i>N</i>,<i>N</i>-dimethyl-<i>N</i>,<i>N</i>,<i>N</i>-trimethyl-6-<i>O</i>-glycol chitosan (GCPQ) nanoparticles, and have evidenced our approach in three separate disease states (visceral leishmaniasis, candidiasis, and aspergillosis) using industry standard models of the disease in small animals. The oral bioavailability of AmB-GCPQ nanoparticles is 24%. In all disease models, AmB-GCPQ nanoparticles show comparable efficacy to parenteral liposomal AmB (AmBisome). Our work thus paves the way for others to use nanoparticles to achieve a specific targeted delivery of drug to key organs via the oral route. This is especially important for drugs with a narrow therapeutic index